Steroido(3,4-c)pyrazoles of the 5alpha- and 5beta-androstane series



United States Patent ABSCT OF THE DISCLOSURE Steroido[3,4-c]pyrazoles ofthe Socand SB-androstane series, having hormonal properties, areprepared by treating with hydrazine the corresponding4-hydroxy-methylene-3-oxo-steroids. The latter intermediates are alsonovel compounds having hormonal properties and are prepared byformylation of 3-oxo-steroids appropriately blocked in the 2-position.

This invention relates to novel steroid compounds and in particular isconcerned with androstano[3,4-c]pyrazoles, intermediates therefor andpreparation thereof,

The final products of the invention have the following general formula;

3,458,504 Patented July 29., 1969 The compounds of Formula I areprepared by reacting with hydrazine a compound of the formula CHOHwherein R and R have the meanings given hereinabove, also includingcompounds of Formula II having a double bond in the 1,2-position, Rbeing hydrogen.

The compounds of Formula II are also within the purview of the inventionand are in turn prepared by introducing a hydroxymethylene group intothe 4-position of a corresponding 3-oxo-steroid having a double bond inthe 1,2-position or two lower-alkyl groups in the 2-position whichprevent reaction at the 2-position. Such starting materials are of theformulas:

and

wherein R and R have the meanings given hereinabove.

The compounds of Formulas III and IV are treated with a lower-alkylformate in the presence of a strong base, e.g., an alkali metalalkoxide, amide or hydride, for example sodium ethoxide, sodium amideand sodium hydride and the like, under anhydrous conditions, to give analkali metal salt of a compound of Formula II. Acidification then givesthe free enol of Formula H.

The compounds of Formulas I and II having a double bond in the1,2-position can be hydrogenated catalytically, e. g., with palladium oncarbon, to produce the corresponding compounds saturated in the1,2-position.

The compounds of Formulas I and II can belong either to the5a-androstane or SB-androstane series.

The compounds of Formula I are basic in nature and thus formacid-addition salts when treated with moderate to strong inorganic ororganic acids. Although pharmaceutically acceptable, water-soluble saltsare preferred, all salts are useful as intermediates in the preparationof and characterizing derivatives of the free bases. These salts are thefull equivalents of the corresponding free bases insofar as thephysiological properties inherent in the cation are concerned. Both thefree base and salt forms are considered to be one and the sameinvention.

The compounds of Formula II are acidic in nature and thus form saltswith strong bases such as alkali metal hydroxides, alkoxides orhydrides. Illustrative salts are the sodium, potassium and calciumsalts. The salts are the full equivalents of the corresponding freebydroxymethylene compounds insofar as their physiological properties areconcerned and their utility as intermediates.

The structures of the compounds of the invention were established by themodes of synthesis, by elementary analysis and by ultraviolet andinfrared spectral data.

Endocrinological evaluation of the compounds of Formula I has shown thatthey possess useful harmonal properties; in particular they are usefulas estrogenic, progestational and hypocholesteremic agents. They areeffective at dose levels of -50 mg./kg. when administered subcutaneouslyor orally, and are prepared for use in the manner by which steroidalhormones are conventionally formulated.

The compounds of Formula II are not only useful as intermediates in thepreparation of the compounds of Formula I, but have been shown byendocrinological evaluation to have useful hormonal properties, inparticular pituitary inhibiting and anabolic activities. They areeffective at dose levels of 2-30 mg./kg. when administeredsubcutaneously or orally, and are prepared for use in the manner bywhich steroidal hormones are conventionally formulated.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 (a) 4-hydroxymethylene-17a-methyl-5u-androsten-17(3- ol-3-one[11; R is CH R is H, A 5a-H].To a solution of 42.0 g. of17B-hydroxy-17a-methyl-5ot-1-androsten-3-one (M.P. 152-154 C. whenrecrystallized from acetone-hexane) in 300 ml. of pyridine was added30.0 g. of sodium methoxide, 100 ml. of pyridine and 40 ml. of ethylformate. The reaction mixture was stirred under nitrogen for a fewminutes and allowed to stand at room temperature under nitrogen for twodays. Ice-water was then added followed by an excess of concentratedhydrochloric acid. The product was extracted with methylene dichloride,and the methylene dichloride extracts were washed with water and with 2liters of 0.4 N sodium hydroxide. The solid sodium salt which formed wascollected by filtration, Washed with water, and added to 500 ml. of 2 Nhydrochloric acid. The acid product was extracted with ether and theether extracts washed with 200 m1. of 5% sodium bicarbonate solution and200 ml. of saturated sodium chloride solution dried over anhydrousmagnesium sulfate and concentrated to about 50 ml. There separated 28.65g. of 4-hydroxymethylene-17amethyl-5a-1-androsten-l7,B-ol-3one. M.P.138-140" C. A sample when recrystallized from acetonitrile was obtainedin the form of colorless needles, M.P. 139l4l C.; [a] =+132.0 (1% inchloroform).

(b) 175 hydroxy-l7a-methyl-5a-l-androsteno[3,4-c] pyrazole [1; R is CHR' is H, A 5a-H].--To a solution of 1.24 g. of4-hydroxymethylene-l7a-methyl-5a-1- androsten-l7/8-ol-3-one in 20 ml. ofethanol was added 0.21 g. of hydrazine hydrate. The reaction mixture wasrefluxed for two hours and then concentrated by distillation on a steambath. Water was added to the residue, and the product was collected byfiltration, washed with water and dried to give 1.20 g. of 173-hydroxy-17a-methyl-Sa-l-androsteno[3,4-c]pyrazole, M.P. 247.4257.4 C.when recrystallized from an ethanol-methanol mixture.

EXAMPLE 2 (a) 4hydroxymethylene-2,2,l7a-trimethyl-5a-androstan-l75-ol-3-one [11; R andR' are CH SOL-H] was prepared from 3.32 g. of2,2,17a-trimethyl-ia-androstan- 17,8-01-3-one (M.P. 112-114 C. whenrecrystallized from pent-ane-ether), sodium methoxide (from 0.5 g. ofsodium) and 7 ml. of ethyl formate in 50 ml. of pyridine according tothe procedure described above in Example 1, part (a). There was thusobtained 1.23 g. of 4-hydroxymethylene-2,2,l7a-trimethyl-Sa-andmstan17,8 0l- 3-one, M.P. 164-170 C.

(b) 175 hydroxy-2,2,17tx-trimethyl-5a-androstano[3, 4-c]pyrazole [1; Rand R are CH Sou-H] was prepared from 1.12 g. of4-hydroxymethylene-2,2,17a-trimethyl- 5a-androstan-17B-ol-3-one and 0.17g. of hydrazine hydrate in ethanol according to the procedure describedabove in Example 1, part (b). The product was recrystallized from etherto give 17,B-hydroxy-2,2,l7a-trimethyl-5a-androstano[3,4-c]pyrazole,M.P. 255.6-264.6 C., [a] =+l5.9 (1% in pyridine).

EXAMPLE 3 (a) 4-hydroxymethylene 17a methyl-Sa-androstan- 17fl'ol-3-one[11; R is CH R is H, 5a-H].--A solution of 6.60 g. of4-hydroxymethylene-17a-methyl-5a-l-androsten-17fl-ol-3-one (Example 1a)in 300 ml. of ethanol was hydrogenated in the presence of 0.50 g. of 10%palladium on carbon catalyst. After the uptake of hydrogen had ceased,the reaction mixture was filtered and the solvent removed bydistillation. The residue was recrystallized from acetonitrile to give4-hydroxymethylene- 17a-methyl-5a-androstan-17B-ol-3-one, colorlessprisms, M.P. 146147 C.; [u] =+Z5.l (1% in chloroform).

(b) 17fl-hydroxy-17u-methyl 5oz androstano[3,4-c] pyrazole [1; R is CH Ris H, Soc-H] was prepared by catalytic hydrogenation of 2.44 g. of17;.8-hydroxy-17amethyl-5u-l-androsteno[3,4-c]pyrazole (Example 1b)according to the procedure of Example 3(a) above. There was obtained1.77 g. of 175-hydroxy-17a-methy1 5u-androstano[3,4-c]pyrazole, M.P.259-269 C. A sample when recrystallized from an ethanol-methanol mixturehad the M.P. 264.2-272.4 C.; [a] =7.4 (1% in chloroform).

17B-hydroxy 17a methyl-Sa-androstano[3,4-c]pyrazole can also be obtainedby treating 4-hydroxymethylene- 17a-methyl-5a-androstan-l7B-ol-3-onewith hydrazine according to the procedure of Example 1, part (b).

EXAMPLE 4 (a) 4 hydroxymethylene-Sfi-1-androsten-17fl-ol-3-one [11; Rand R are H, A 5,6-H].A solution of 5.25 g. of5fl-1-androsten-l7B-ol-3-one (M.P. 199-202 C., colorless rods from ethylacetate-hexane) in 400 ml. of benzene was distilled under nitrogen untilml. of solvent had been removed. The solution was cooled to roomtemperature, and 5 ml. of ethyl formate and 2.00 g. of sodium methoxidewere added. The reaction mixture was stirred under nitrogen for 30minutes and kept at room temperature under nitrogen for 44 hours. Thesolid product was collected, washed with ether and suspended in water.To the suspension 1 liter of cold water containing 10 ml. of acetic acidwas added. The product was collected by filtration, washed with waterand dried to give 5.3 g. of 4-hydroxymethylene-5fl-1-androsten-17B-ol-3-one, M.P. 122-127" C. Repeated recrystallization from aqueous ethanolgave a sample in the form of pale yellow needles, M.P. 15l152 C.; [a]:|131.4 (1% in chloroform).

(b) hydroxy 5,8-l-androsteno[3,4-c1pyrazole [1; R and R are H, A 5B-H].Amixture of 1.297 g. of 4-hyd-roxymethylene-Sfi-l-androsten-l7fi-ol-3-one, 1 ml. of hydrazinehydrate, 50 ml. of tetrahydrofuran and 10 ml. of ethanol was heated toboiling on a steam bath. The reaction mixture was kept at roomtemperature for 90 hours, and the solvent was then removed in vacuo. Theresidue was recrystallized from aqueous ethanol to give 1.17 g. of17fi-hydroxy-5fi-1-androsteno[3,4-c]pyrazole, M.P. 263-266 C. Furtherrecrystallization gave a sample in the form of pale yellow crystals,M.P. 267.6-268.4 C.; [a] =+91 (1% in ethanol).

(0) 1713 hydroxy 5/3 androstano[3,4 c]pyrazole [I; R and R are H, 55-H]can be prepared by catalytic hydrogenation of17B-hydroxy-SB-l-androsteno[3,4-c]py-razole by the procedure of Example3.

EXAMPLE 5 (a) 4 hydrOXymethyIene-Sa-l-androsten-17 B-o1-3-one [11; R andR are H, N, SOL-H] was prepared from 20.0 g. of5a-1-androsten-l7/3-ol-3-one (M.P. l52-l56 C.) and sodium methoxide(from 4.6 g. of sodium) in methanolpyridine solution according to theprocedure of Example 1, part (a). The product was recrystallized fromaqueous acetonitrile to give 4-hydroxymethylene-Sa-l-androsten-17fi-ol-3-one, M.P. 1S2.6154.8 C.; [a] =|l6l.8 (1% in chloroform).

(b) 17,3-hydroxy-5a-l-androsteno[3,4-c1pyrazole [1; R and R are H, N,5oL-H] can be prepared by treating 4 hydroxyrnethylene 5a-1-androsten-l78-ol-3-one with hydrazine according to the procedure of Example 1, part(b).

(c) 17B-hydroxy-5u-androstano[3,4-c]pyrazole [1; R and R are H, Soc-H]can be prepared by catalytic hydrogenation of17B-hydroxy-5u-l-androsteno[3,4-c]pyrazole by the procedure of Example3.

EXAMPLE 6 ol-3-one 3-ethylene glycol ketal. Removal of the ketal groupwith acid then gives the desired 17a-ethynyl-5a-landrosten-17B-ol-3-one.

(b) 17/3 hydroxy-17a-ethynyl-5a-1-androsteno[3,4-c] pyrazole [1; R isCECH, R is H, A Soc-H] can be prepared by treating4-hydroxyrnethylene-l7a-ethynyl-5a-landrosten-l7fl-ol-3-one withhydrazine according to the procedure of Example 1, part (b).

EXAMPLE 7 (a) 4 hydroxymethyle-ne 2,2-dimethyl-l7a-ethynyl-Sa-androstan-17fl-ol-3-one [11; R is CECH, R is CH Soc-H] can 'beprepared as follows: 2,2-'dimethyl-5a-androstan-17fi-ol-3-one isconverted to its 3-ethylene glycol ketal and the latter oxidized withchromic oxide to the 3-ketal of 2,2-dimethyl-5a-androstane-3,17dione,which is then ethynylated with ethynyllithium to give the 3-ketal of 2,2dimethyl-17a-ethynyl-5a androstan-17fi-ol-3-one. Acid cleavage of theketal followed by reaction with ethyl formate and sodium methoxideaccording to the procedure of Example 1, part (a), gives the desired4-hydroxymethylene 2,2 dimethyl 17a-ethynyl-5a-androstan-17B-ol-3-one.

(b) 17,8 hydroxy-2,2-dimethyl-l7a-ethynyl-5a-androstano[3,4-c]pyrazole[1; R is CECH, R is CH Six-H] can be prepared by treating4-hydroxymethylene-2,2-dimethyl 17oz ethynyl 5a androstan-17 8-ol-3-onewith hydrazine according to the procedure of Example 1, part (b).

EXAMPLE 8 17,8 hydroxy-5u-androstano[3,4-c]pyrazole (Example 50) whentreated with cyanic acid (potassium cyanate and hydrochloric acid) isconverted to 175-hydroxy-5aandrostano[3,4 c]pyrazole N carboxamide. Thelatter with chromic oxide in acetic acid solution is oxidized to 17 oxo5a-androstano[3,4-c]pyrazole-N-carboxamide, which when heated withethanolic hydrogen chloride is converted to 17 oxo 5a-androstano[3,4-c]pyrazole. 17- oxo-Sa-androstano[3,4-c]pyrazole can be caused to reactwith an alkali metal 'acetylide to afford 17/3-hydroxy-17a- 6ethynyl-Sa-androsttmo[3,4-c]pyrazole [I; R is CECH, R is H, SOC-H].

I claim:

1. (A) compound of the formula wherein R is hydrogen, lower-alkyl orlower-alkynyl; and R is hydrogen or lower-alkyl; or (B) A compound ofthe above formula having a double bond in the 1,2-position, R beinghydrogen.

2. A compound according to claim 1 wherein R is hydrogen or methyl.

3. 17,8 hydroxy-17a-methyl-5a-l-androsteno[3,4-c] pyrazole, according toclaim 2 wherein R is methyl and R is hydrogen, and there is a doublebond in the 1,2-position.

4. 17 3 hydroxy 2,2,17oc trimethyl 5u-androstano [3,4-c]pyrazole,according to claim 2 wherein R and R are methyl.

5. hydroxy 17cc methyl-5a-androstano[3,4-c] pyrazole, according to claim2 wherein R is methyl and R is hydrogen.

6. 175 hydroxy 5fl-1-androsteno[3,4-c] pyrazole, according to claim 2wherein R and R are hydrogen, and there is a double bond in the1,2-position.

7. (A) A compound of the formula wherein R is hydrogen, lower-alkyl orlower-alkynyl; and R is lower-alkyl; or (B) a compound of the aboveformula having a double bond in the 1,2-position, R being hydrogen.

8. A compound according to claim 7 wherein R is hydrogen or methyl.

9. 17,8 hydroxy-4-hydroxymethylene-l7oc-methyl-5u- 1-androsten-3-one,according to claim 8 wherein R is methyl and R is hydrogen, and there isa double bond in the 1,2-position.

10. 17,8 hydroxy 4hydroXymethylene-2,2,l7a-trimethyl-5a-androstan-3-one, according toclaim 8 wherein R and R are methyl. I

11. 17,3 hydroxy-4-hydroxymethylene-5 3-1-androsten- 3-one, according toclaim 8 wherein R and R are hydrogen, and there is a double bond in the1,2-position.

12. 17,3 hydroxy-4-hydroxymethylene-5a-l-androsten- 3-one, according toclaim 8 wherein R and R are hydrogen, and there is a double bond in the1,2-position.

References Cited Clinton et al., Chem. & Ind. pp. 2099-2100 (1961).

Clinton et al., J. Org. Chem. 27 pp. 2800-01 (1962).

Sciaky et al., Tetrahedron Letters No. 28, pp. 1839-40 (1964).

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 15850 1 Dated July 29, 1969 In n (5) Raymond 0. Clinton It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 3, line 8, "harmonal" should read --hormona1--; line 28,"5o-androsten-" should read -5a-l-androsten- Column 5, line 17, "Rshould read --R'--; line 30, "glycol as" should read --glycol and---.

SIGRE 35 I. AUG 1 mm 2. am, :3. EMU-Emir fi missionuof PatentsAttestingoffic

